The following documents are cited herein:
1. Kerr, J. F. R., Wyllie A. H., Currie, A. R. (1992), “Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.” British Journal of Cancer 26: 239-257;
2. Fadok (1998) J. Clin. Invest., 101, 890-898;
3. Fadok V. A., Voelker D. P., Campbell P. A., Cohen, J. J., Bratton, D. L., Henson, P. M. (1992), “Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.” Journal of Immunology 148:2207-2216;
4. Fadok V. A., Bratton, D. L., Rose, D. M., Pearson, A., Exekewitz R. A. B., Henson, P. M. (2000), “A receptor for phosphatidylserine-specific clearance of apoptotic cells,” Nature 405:85-90;
5. Monastra et al. Neurology (1993) 48:153-163;
6. Zanotti et al., 1989;
7. Delwaide et al., (1986) Acta Neurol. Scand.; 73: 136-140.
8. Yechezkel Barenholz and Daan J. A. Chromeline, Liposomes as Pharmaceutical Dosage Forms, and literature cited therein, for example New, R. C., “Liposomes: A Practical Approach,” IRL Press at Oxford University Press, Oxford, England (1990), and Nassander, U. K., et al., In: “Biodegradable Polymers as Drug Delivery Systems” (M. Chasin and R. Langer, eds.) Marcel Dekker Inc., New York 1990, pages 261-338;
9. Griffin W S T, Stanley, L. C., Ling, C., White, L., Macleod, V. Perrot L. H J., White,
C. L., Araoz, C., (1989), Brain interleukin 1 and S-100 immunoreactivity are elevated in Down's syndrome and Alzheimer's disease, Proceedings of the National Academy of Sciences USA 86: 7611-7615;
10. Mogi M., Harada, M., Narabayashi, H., Inagaki, H., Minami, M., Nagatsu T., (1996) “Interleukin (IL)-1 beta, IL-1, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease,” Neuroscience Letters 211: 13-16;
11. Murray, C. A., Lynch, M. A., (1998) “Evidence that increase hippocampal expression of the cytokine interleukin-1.beta. is a common trigger for age and tress-induced impairments in long-term potentiation,” Journal of Neuroscience 18:2974-2981;
12. Bliss, T. V. P., Collinridge, G. L., (1993) “A synaptic model of memory: long-term potentiation in the hippocampus,” Nature 361:31-39.
Two mechanisms of cell death in the body are recognized, necrosis and apoptosis. Apoptosis is the process of programmed cell death, described by Kerr et al. (1992) by which steady-state levels of the various organ systems and tissues in the body are maintained as continuous cell division is balanced by cell death. Cells undergoing apoptosis often exhibit distinct morphological changes such as pronounced decrease in cell volume, modification of the cytoskeletons resulting in pronounced membrane blebbing, a condensation of the chromatin, and degradation of the DNA into oligonucleosomal fragments. Following these morphological changes, an apoptotic cell may break up into a number of small fragments known as apoptotic bodies, consisting essentially of membrane-bound bodies containing intact organelles, chromatin etc. Apoptotic cells and apoptotic bodies are normally rapidly removed from the body by phagocytosis principally by macrophages and dendritic cells, before they can become lysed and release their potentially pro-inflammatory intracellular contents.
Macrophages which have ingested apoptotic cells and/or apoptotic bodies (e.g. phagocytosis) appear to inhibit pro-inflammatory cytokine production (Fadok et al., 1998) and thus may down-regulate a Th-1 response in a patient's immune system. Such down-regulation can also be achieved following injection of apoptotic cells or bodies, or following injection of cells susceptible to accelerated apoptosis.
During apoptosis, phosphatidylserine becomes exposed externally on the cell membrane (Fadok et al. (1992)) and this exposed phosphatidylserine binds to specific receptors to mediate the uptake and clearance of apoptotic cells in mammals (Fadok et al (2000)). The surface expression of phosphatidylserine on cells is a recognized method of identification of apoptotic cells.
Monastra et al. (1993) describe that the administration of phospholipid phosphatidylserine (PS) derived from bovine cortex (BC-PS) may have an effect on adoptively transferred Experimental Autoimmune Encephalomyelitis (EAE) in SJL/J mice. However, an extremely high dose of BC-PS, 30 mg/kg, was injected intraperitoneally on a daily basis. An equivalent dose of liposomes given to a human (greater than 2 grams per average individual) would be potentially toxic, expensive and therefore impractical and undesirable. Such quantities would be active, if at all, as drugs, and would be too large to act as immune system modifiers.
Oral administration of PS has been used both in animal models to improve spatial memory, in amounts of 50 mg/day (Zanotti et al., 1989), and in humans to treat Alzheimer's
disease, in amounts of 300 mg/day (Delwaide et al., 1986) and showed statistically significant improvements in PS treated subjects as compared with placebo.